APPLICATION OF A PROTEIN-SYNTHESIS INHIBITOR INTO THE VENTRAL TEGMENTAL AREA, BUT NOT THE NUCLEUS-ACCUMBENS, PREVENTS BEHAVIORAL SENSITIZATION TO COCAINE

Recent evidence implicates a crucial role for the ventral tegmental ar ea (VTA) in the initiation of behavioral sensitization produced by rep eated psychostimulant exposure, while changes in the nucleus accumbens (NAcc) are not critical during the initiation stage. We investigated whether the development of behavioral sensitization to repeated daily cocaine could be prevented by daily administration of the protein synt hesis inhibitor, anisomycin, delivered onto VTA neurons. Rats were giv en five daily treatments as follows: obturators containing crystalline anisomycin or no compound (sham) were placed directly into the VTA 15 min prior to a saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) inj ection. After withdrawal for 8-9 days, the locomotor response to the s ame dose of saline or cocaine was monitored. No differences in the loc omotor response to an acute saline challenge were found across the fou r groups. Animals given sham treatments in the VTA and daily cocaine d emonstrated a significant augmentation in the locomotor response to a cocaine challenge compared to saline controls. Anisomycin treatments a lone produced no effects on acute cocaine-induced locomotion. Further, a cocaine challenge in animals receiving daily anisomycin and cocaine elicited a non-augmented response similar to that of saline controls. Thus, the sensitized locomotor response to a cocaine challenge in dai ly cocaine pretreated animals was completely blocked by daily anisomyc in treatment in the VTA. When daily anisomycin was administered into t he NAcc along with daily cocaine, no blockade of behavioral sensitizat ion was observed. These results provide support for a critical role of long-term changes in gene expression in the vicinity of VTA neurons m ediating the development of sensitization to psychostimulants. (C) 199 5 Wiley-Liss, Inc.